PDF(Pubmed)
Abstract：
Infection by Kaposi sarcoma-associated herpesvirus (KSHV) can cause severe consequences, such as cancers and lymphoproliferative diseases. Whole inactivated viruses (WIV) with chemically destroyed genetic materials have been used as antigens in several licensed vaccines. During KSHV productive replication, virus-like vesicles (VLVs) that lack capsids and viral genomes are generated along with virions. Here, we investigated the immunogenicity of KSHV VLVs produced from a viral mutant that was defective in capsid formation and DNA packaging. Mice immunized with adjuvanted VLVs generated KSHV-specific T cell and antibody responses. Neutralization of KSHV infection by the VLV immune serum was low but was markedly enhanced in the presence of the complement system. Complement-enhanced neutralization and complement deposition on KSHV-infected cells was dependent on antibodies targeting viral open reading frame 4 (ORF4). However, limited complement-mediated enhancement was detected in the sera of a small cohort of KSHV-infected humans which contained few neutralizing antibodies. Therefore, vaccination that induces antibody effector functions can potentially improve infection-induced humoral immunity. Overall, our study highlights a potential benefit of engaging complement-mediated antibody functions in future KSHV vaccine development. IMPORTANCE KSHV is a virus that can lead to cancer after infection. A vaccine that prevents KSHV infection or transmission would be helpful in preventing the development of these cancers. We investigated KSHV VLV as an immunogen for vaccination. We determined that antibodies targeting the viral protein ORF4 induced by VLV immunization could engage the complement system and neutralize viral infection. However, ORF4-specific antibodies were seldom detected in the sera of KSHV-infected humans. Moreover, these human sera did not potently trigger complement-mediated neutralization, indicating an improvement that immunization can confer. Our study suggests a new antibody-mediated mechanism to control KSHV infection and underscores the benefit of activating the complement system in a future KSHV vaccine.
摘要：
卡波西肉瘤相关疱疹病毒（KSHV）感染可引起严重后果，如癌症和淋巴增生性疾病。具有化学破坏的遗传物质的全灭活病毒（WIV）已被用作几种许可疫苗的抗原。在KSHV生产性复制期间，缺乏衣壳和病毒基因组的病毒样囊泡(VLV)与病毒体一起产生。这里,我们研究了由衣壳形成和DNA包装缺陷的病毒突变体产生的KSHVVLV的免疫原性.用佐剂化的VLV免疫的小鼠产生KSHV特异性T细胞和抗体应答。VLV免疫血清对KSHV感染的中和作用较低，但在补体系统存在下明显增强。在KSHV感染的细胞上补体增强的中和和补体沉积依赖于靶向病毒开放阅读框4(ORF4)的抗体。然而,在一小群KSHV感染人群的血清中检测到补体介导的增强作用有限,这些人群中的中和抗体很少.因此,诱导抗体效应功能的疫苗接种可以潜在地改善感染诱导的体液免疫。总的来说,我们的研究强调了在未来的KSHV疫苗开发中使用补体介导的抗体功能的潜在益处.重要性KSHV是一种感染后可导致癌症的病毒。预防KSHV感染或传播的疫苗将有助于预防这些癌症的发展。我们研究了KSHVVLV作为疫苗接种的免疫原。我们确定通过VLV免疫诱导的靶向病毒蛋白ORF4的抗体可以参与补体系统并中和病毒感染。然而,在KSHV感染的人的血清中很少检测到ORF4特异性抗体。此外，这些人血清不能有效触发补体介导的中和作用，表明免疫接种可以带来的改善。我们的研究提出了一种新的抗体介导的机制来控制KSHV感染，并强调了在未来的KSHV疫苗中激活补体系统的益处。
